Gündel Daniel, Allmeroth Mareli, Reime Sarah, Zentel Rudolf, Thews Oliver
Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle (Saale).
Institute of Organic Chemistry, Johannes Gutenberg-University, Mainz, Germany.
Int J Nanomedicine. 2017 Aug 3;12:5571-5584. doi: 10.2147/IJN.S136952. eCollection 2017.
Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis.
Six different -(2-hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO ≈1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately.
The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin-dependent endocytosis.
The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient.
聚合物纳米颗粒能够将化疗药物选择性地转运至肿瘤组织。这些纳米载体必须被细胞摄取才能释放药物。此外，肿瘤通常表现出病理代谢特征（缺氧和酸中毒），这可能会影响聚合物的内吞作用。
在两种不同的肿瘤模型中分析了六种不同的基于甲基丙烯酸-(2-羟丙酯)(HPMA)的聚合物结构（均聚物以及带有含疏水侧链的甲基丙烯酸月桂酯的无规共聚物和嵌段共聚物），其分子量和尺寸各不相同。在缺氧（pO₂≈1.5 mmHg）和酸性（pH 6.6）条件下测量荧光标记聚合物的细胞摄取。通过使用特异性抑制剂，分别分析了不同的内吞途径（巨胞饮作用以及网格蛋白介导的、发动蛋白依赖性、胆固醇依赖性内吞作用）。
当前结果表明，聚合物的摄取取决于所使用的分子结构、分子量和肿瘤细胞系。在AT1细胞中，无规共聚物的摄取比均聚物强五倍，而在Walker-256细胞中，所有聚合物的摄取都要强得多，但这与分子结构和尺寸无关。酸中毒增加了AT1细胞中无规共聚物的摄取，但降低了均聚物和嵌段共聚物的细胞内积累。缺氧降低了Walker-256细胞中所有聚合物的摄取。亲水性聚合物（均聚物和嵌段共聚物）通过所研究的所有内吞途径被摄取，而亲脂性更强的无规共聚物似乎优先通过胆固醇依赖性和发动蛋白依赖性内吞作用被摄取。
该研究表明，聚合物的众多参数（结构、尺寸）以及肿瘤的参数（灌注、血管通透性、pH、pO₂）会调节药物递送，这使得为个体患者选择合适的聚合物变得困难。
